Crystapen Injection

Benzylpenicillin sodium BP available as 600 mg and 1200 mg vials.

White crystalline, water-soluble sterile powder for injection.

Crystapen is indicated for most wound infections, pyogenic infections of the skin, soft tissue infections and infections of the nose, throat, nasal sinuses, respiratory tract and middle ear, etc.

It is also indicated for the following infections caused by penicillin-sensitive microorganisms: Generalised infections, septicaemia and pyaemia from susceptible bacteria. Acute and chronic osteomyelitis, sub-acute bacterial endocarditis and meningitis caused by susceptible organisms. Suspected meningococcal disease. Gas gangrene, tetanus, actinomycosis, anthrax, leptospirosis, rat-bite fever, listeriosis, severe Lyme disease, and prevention of neonatal group B streptococcal infections. Complications secondary to gonorrhoea and syphilis (e.g. gonococcal arthritis or endocarditis, congenital syphilis and neurosyphilis). Diphtheria, brain abscesses and pasteurellosis.

Consideration should be given to official local guidance (e.g. national recommendations) on the appropriate use of antibacterial agents.

Susceptibility of the causative organism to the treatment should be tested (if possible), although therapy may be initiated before the results are available.

Route of administration:

Intramuscular, intravenous.

Preparation of solutions:

Pharmaceutical preparation

Only freshly prepared solutions should be used. Reconstituted solutions of benzylpenicillin sodium BP are intended for immediate administration.

600 mg vial

Intramuscular injection: 600 mg (1 mega unit) is usually dissolved in 1.6 to 2.0 ml of Water for Injections BP.

600 mg and 1200 mg vials

Intravenous Injection: A suitable concentration is 600 mg (1 mega unit) dissolved in 4 to 10 ml of Water for Injections BP or Sodium Chloride Injection BP and 1200 mg (2 mega units) dissolved in at least 8 ml of Sodium Chloride Injection BP or Water for Injections BP.

Intravenous Infusion: It is recommended that 600 mg (1 mega unit) should be dissolved in at least 10 ml of Sodium Chloride Injection BP or Water for Injections BP and 1200 mg (2 mega units) should be dissolved in at least 20 ml of Sodium Chloride Injection BP or Water for Injections BP.

Sodium overload and/or heart failure may occur if benzylpenicillin sodium BP is administered in sodium-containing solvents to patients who suffer from renal failure and/or heart failure. Therefore, for such patients, benzylpenicillin sodium BP should not be reconstituted in sodium-containing liquids such as Sodium Chloride Injection BP or Ringer's solution.

Dosage and administration:

The following dosages apply to both intramuscular and intravenous injection.

Alternate sites should be used for repeated injections.

Adults

600 to 3,600 mg (1 to 6 mega units) daily, divided into 4 to 6 doses, depending on the indication. Higher doses (up to 14.4 g/day (24 mega units) in divided doses) may be given in serious infections such as adult meningitis by the intravenous route.

In bacterial endocarditis, 7.2 to 12 g (12 to 20 mega units) or more may be given daily in divided doses by the intravenous route, often by infusion.

Doses up to 43.2 g (72 mega units) per day may be necessary for patients with rapidly spreading gas gangrene.

High doses should be administered by intravenous injection or infusion, with intravenous doses in excess of 1.2g (2 mega units) being given slowly, taking at least one minute for each 300 mg (0.5 mega unit) to avoid high levels causing irritation of the central nervous system and/or electrolyte imbalance.

High dosage of benzylpenicillin sodium BP may result in hypernatraemia and hypokalaemia unless the sodium content is taken into account.

For the prevention of Group B Streptococcal disease of the newborn, a 3 g (5 mega units) loading dose should be given to the mother initially, followed by 1.5 g (2.5 mega units) every 4 hours until delivery.

Children aged 1 month to 12 years

100 mg/kg/day in 4 divided doses; not exceeding 4 g/day.

Infants 1-4 weeks

75 mg/kg/day in 3 divided doses.

Newborn Infants

50 mg/kg/day in 2 divided doses.

Meningococcal disease

Suspected meningococcal disease

If meningococcal disease is suspected general practitioners should give a single dose of benzylpenicillin sodium BP, before transferring the patient to hospital, as follows:

Premature babies and neonates

Dosing should not be more frequent than every 8 or 12 hours in this age group, since renal clearance is reduced at this age and the mean half-life of benzylpenicillin may be as long as 3 hours.

Since infants have been found to develop severe local reactions to intramuscular injections, intravenous treatment should preferably be used.

Patients with renal insufficiency

For doses of 0.6-1.2 g (1-2 mega units) the dosing interval should be no more frequent than every 8-10 hours.

For high doses e.g. 14.4 g (24 mega units) required for the treatment of serious infections such as meningitis, the dosage and dose interval of benzylpenicillin sodium BP should be adjusted in accordance with the following schedule:

The dose in the above table should be further reduced to 300 mg (0.5 mega units) 8 hourly if advanced liver disease is associated with severe renal failure.

If haemodialysis is required, an additional dose of 300 mg (0.5 mega units) should be given 6 hourly during the procedure.

Elderly Patients

Elimination may be delayed in elderly patients and dose reduction may be necessary.

Allergy to penicillins. Hypersensitivity to any ingredient of the preparation.

Cross allergy to other beta-lactams such as cephalosporins should be taken into account.

600 mg benzylpenicillin contains 1.68 mmol of sodium. Massive doses of Benzylpenicillin Sodium BP can cause hypokalaemia and sometimes hypernatraemia. Use of a potassium-sparing diuretic may be helpful. In patients undergoing high-dose treatment for more than 5 days, electrolyte balance, blood counts and renal functions should be monitored.

In the presence of impaired renal function, large doses of penicillin can cause cerebral irritation, convulsions and coma.

Skin sensitisation may occur in persons handling the antibiotic and care should be taken to avoid contact with the substance.

It should be recognised that any patient with a history of allergy, especially to drugs, is more likely to develop a hypersensitivity reaction to penicillin. Patients should be observed for 30 minutes after administration and if an allergic reaction occurs the drug should be withdrawn and appropriate treatment given.

Delayed absorption from the intramuscular depot may occur in diabetics.

Prolonged use of benzylpenicillin may occasionally result in an overgrowth of non-susceptible organisms or yeast and patients should be observed carefully for superinfections.

Pseudomembranous colitis should be considered in patients who develop severe and persistent diarrhoea during or after receiving benzylpenicillin. In this situation, even if Clostridium difficile is only suspected, administration of benzylpenicillin should be discontinued and appropriate treatment given.

The efficacy of oral contraceptives may be impaired under concomitant administration of benzylpenicillin sodium BP, which may result in unwanted pregnancy. Women taking oral contraceptives should be aware of this and should be informed about alternative methods of contraception.

There is reduced excretion of methotrexate (and therefore increased risk of methotrexate toxicity) when used with benzylpenicillin sodium BP.

Probenecid inhibits tubular secretion of benzylpenicillin sodium BP and so may be given to increase the plasma concentrations.

Penicillins may interfere with:

• Urinary glucose tests

• Coomb's tests

• Tests for urinary or serum proteins

• Tests which use bacteria e.g. Guthrie test

Benzylpenicillin sodium BP has been taken by a large number of pregnant women and women of childbearing age without an increase in malformations or other direct or indirect harmful effects on the foetus having been observed.

Although it is not known if benzylpenicillin sodium BP may be excreted into the breast milk of nursing mothers, it is actively transported from the blood to milk in animals and trace amounts of other penicillins in human milk have been detected.

None

Blood and Lymphatic System Disorders

Rare (0.01% - 0.1%)

Haemolytic anaemia and granulocytopenia (neutropenia), agranulocytosis, leucopenia and thrombocytopenia, have been reported in patients receiving prolonged high doses of benzylpenicillin sodium BP (eg. Subacute bacterial endocarditis).

Immune System Disorders

Very Common (>10%)

Patients undergoing treatment for syphilis or neurosyphilis with benzylpenicillin may develop a Jarisch-Herxheimer reaction.

Common (1-10%)

Hypersensitivity to penicillin in the form of rashes (all types), fever, and serum sickness may occur (1-10% treated patients). These may be treated with antihistamine drugs.

Rare (0.01%-0.1%)

More rarely, anaphylactic reactions have been reported (<0.05% treated patients).

Nervous System Disorders

Rare (0.01%-0.1%)

Central nervous system toxicity, including convulsions, has been reported with massive doses over 60 g per day and in patients with severe renal impairment.

Renal and Urinary Disorders

Rare (0.01%-0.1%)

Interstitial nephritis has been reported after intravenous benzylpenicillin sodium BP at doses of more than 12 g per day.

Excessive blood levels of benzylpenicillin sodium BP can be corrected by haemodialysis.

Pharmacotherapeutic group: Beta-lactamase sensitive penicillins.

ATC code: J01 CE01.

General Properties:

Benzylpenicillin sodium BP is a beta-lactam antibiotic. It is bacteriocidal by inhibiting bacterial cell wall biosynthesis.

Breakpoints:

The tentative breakpoints (British Society for Antimicrobial Chemotherapy, BSAC) for benzylpenicillin sodium BP are as follows:

S = Susceptible, I = Intermediate susceptibility, R = Resistant

Susceptibility:

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. The following table gives only approximate guidance on probabilities whether microorganisms will be susceptible to benzylpenicillin sodium BP or not.

* UK data; ** European data, ***Global data

* UK data; ** European data, *** Global data

Other Information:

Known Resistance Mechanisms and Cross-resistance

Penicillin resistance can be mediated by alteration of penicillin binding proteins or development of beta-lactamases.

Resistance to penicillin may be associated with cross-resistance to a variety of other beta lactam antibiotics either due to a shared target site that is altered, or due to a beta-lactamase with a broad range of substrate molecules. In addition to this, cross resistance to unrelated antibiotics can develop due to more than one resistance gene being present on a mobile section of DNA (e.g. plasmid, transposon etc) resulting in two or more resistance mechanisms being transferred to a new organism at the same time.

Benzylpenicillin sodium BP rapidly appears in the blood following intramuscular injection of water-soluble salts and maximum concentrations are usually reached in 15-30 minutes. Peak plasma concentrations of about 12 mcg/ml have been reported after doses of 600 mg with therapeutic plasma concentrations for most susceptible organisms detectable for about 5 hours. Approximately 60% of the dose injected is reversibly bound to plasma protein.

In adults with normal renal function the plasma half-life is about 30 minutes. Most of the dose (60-90%) undergoes renal elimination, 10% by glomerular filtration and 90% by tubular secretion. Tubular secretion is inhibited by probenecid, which is sometimes given to increase plasma penicillin concentrations. Biliary elimination of benzylpenicillin sodium BP accounts for only a minor fraction of the dose.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.

None

Benzylpenicillin sodium BP and solutions that contain metal ions should be administered separately.

Benzylpenicillin sodium should not be administered in the same syringe / giving set as amphotericin B, cimetidine, cytarabine, flucloxacillin, hydroxyzine, methylprednisolone, or promethazine since it is incompatible with these drugs.

Unopened 36 months.

Reconstituted product should be used immediately.

Store below 25°C.

Tubular type III glass vials sealed with bromobutyl rubber plugs with aluminium overseals or plastic 'flip-top' caps. This product is supplied in vials containing 600 mg and 1.2 g of powder in boxes containing 10, 25, 50, and 100 vials, and "GP pack" containing 2 vials of 600 mg.

After contact with skin, wash immediately with water. In case of contact with eyes, rinse immediately with plenty of water and seek medical advice if discomfort persists.

Genus Pharmaceuticals

Park View House

65 London Road

Newbury

Berkshire RG14 1JN

United Kingdom

PL 06831/0213

3 July 2008

3 July 2008